A population of interneurons in dissociated cell cultures of embryonic rat cortex was found to express calretinin immunoreactivity. These neurons are relatively resistant to neurotoxicity induced by either glutamate, NMDA, kainic acid or quisqualate. Similarly, in cerebellar granule cell cultures, an unusual cell type was identified which contained dense calretinin immunoreactivity throughout the cytoplasm and nucleus. This as yet unnamed cell was larger than the average granule cell, had two or three thick dendrites, and at least one varicose process that projected large distances from the perikaryon. In view of our previous cerebellar mapping studies, we believe that this cell type may be a Lugaro cell and/or a Golgi cell. Interestingly, these cells are also relatively resistant to the toxicity observed in granule cells following glutamate, NMDA, kainic acid or quisqualate treatment. The chick retina was incubated in vitro in physiological buffers containing either glutamate (1 mM), NMDA (500 microM), or kainic acid (500 microM). Neuronal degeneration was assessed by the resultant efflux of lactate dehydrogenase to the bathing medium. Treatment with NMDA or glutamate for one hour followed by a 24 hour incubation without drugs revealed the survival of numerous calretinin positive ganglion cells and cells within the inner nuclear layer, in addition to terminals within the inner plexiform layer. Fewer calretinin immunopositive cells were observed following kainic acid treatment (500 microM; 1 hr.) or NMDA for 24 hours. These data imply that the calcium binding protein may confer protection to some neurons against excitotoxic injury. As with other calcium binding proteins, the suggested mechanism for this phenomenon is that calretinin may buffer calcium increases and thereby protect against neurodegeneration.